Absorption

Most opioids are well absorbed via the subcutaneous (SQ) and intramuscular (IM) routes. Although GI absorption tends to be rapid, the oral bioavailability of many opioids is limited by extensive first-pass hepatic metabolism. After large oral (PO) doses, first-pass metabolism can become saturated, and oral bioavailability can be increased. Codeine and oxycodone are two opioids with very good oral bioavailability. The transdermal application of fentanyl is also used in clinical practice.

Distribution

Tissue uptake is variable and depends largely on the drug’s lipophilicity. Highly lipophilic compounds such as fentanyl readily penetrate the central nervous system (CNS), the dura of the spinal column, and tissue “reservoirs.” Opioids exhibit varying degrees of plasma protein binding and typically have large volumes of distribution. Serum concentrations of opioids should not be used as a gauge of clinical effect, because fat, skeletal muscle, lungs, and viscera act as reservoirs after opioid administration. Redistribution from saturated tissue depots can produce persistent or recurrent sedation after discontinuation of prolonged infusions of certain opioids such as fentanyl.⁴

Metabolism

Hepatic metabolism of opioids, typically by the P450 cytochromes, CYP3A4 and CYP2D6, can produce metabolites with either greater or lesser activity than the parent compound. For example, codeine is an active antitussive agent but an ineffective analgesic. The metabolism of codeine to morphine by CYP2D6 reduces its antitussive actions but markedly improves its analgesic properties. Morphine and its semisynthetic derivatives are converted to polar glucuronide metabolites, some of which are active. Metabolism of certain opioids also occurs by similar mechanisms in extrahepatic sites, especially the kidneys.

Elimination

Most opioids and their metabolites are cleared by the kidneys and require dosing adjustments in patients with renal failure. Biliary excretion is limited for most opioids.

Analgesia

Opioids are modulators of pain perception both at the level of the CNS and in the periphery. High concentrations of opioid receptors (largely of the mu subtype) are found in areas of the brain that are associated with analgesia. Cortical effects include decreased reception of painful sensory inputs and enhanced inhibitory outflow from the brain to the sensory nuclei of the spinal cord (dorsal root nuclei). In addition, there is decreased neurotransmission from peripheral afferent pain neurons to the spinal cord and from the spinothalamic tract to the brain. The net effect is decreased perception of nociceptive information. Analgesia is mediated by the mu, delta, and kappa opioid receptor subtypes (see Table 184-1). Morphine also appears to be an effective analgesic (via the mu opioid receptor) when administered intraarticularly.⁵ Tolerance develops to the analgesic effects with repeated use.

Very low doses of naloxone (e.g., 0.25 µg/kg/h) improve the efficacy of morphine analgesia, whereas at higher doses (1 µg/kg/h), analgesia is obliterated by naloxone. The mechanism of this effect is unclear.⁶

Euphoria

The euphoric effects of opioids are typically described as pleasant, floating sensations accompanied by a decrease in anxiety and distress. Not all exogenous opioids induce the same degree of euphoria. Activation of the mu/delta receptor complex in the ventral tegmental area, followed by dopamine release in the mesolimbic system, is most likely responsible for these effects.⁷

The degree of lipophilicity and CNS penetration is directly proportional to the euphoric properties of the opioid. For example, heroin, which enters the CNS with relative ease, is associated with greater euphoria than is the less lipophilic opioid, morphine.⁸ Fentanyl produces euphoric effects akin to those of heroin and is occasionally used as an adulterant in illicitly obtained heroin.⁹ The apparently enhanced euphoric effect of meperidine may be related to its lipophilicity and its ability to alter serotonergic neurotransmission.

By contrast, pentazocine, an agonist-antagonist opioid (i.e., an agent that is both an agonist at kappa receptors and an antagonist at mu opioid receptors), produces dysphoria and psychotomimesis (psychotic symptoms), an effect that most likely is mediated via kappa₂ receptor agonism.¹⁰ Pentazocine also can induce a withdrawal syndrome in opioid-tolerant individuals secondary to its mu opioid receptor antagonist effects. For these reasons, many patients previously exposed to pentazocine will cite allergies to it.

Sedation

Drowsiness and mental clouding are frequent in opioid-using patients. Different opioids are associated with different degrees of sedation despite equianalgesic dosing. Unlike sedative hypnotics, there is little or no associated amnesia unless the patient has been comatose. Electroencephalograms (EEGs) of opioid-sedated patients usually show slow delta waves that resemble sleep.

Respiratory Depression

All opioid agonists produce dose-dependent depression of ventilation. At equianalgesic doses, all opioid agonists lead to a similar degree of respiratory depression.^11,12 In the absence of secondary causes, death from opioid overdose is almost exclusively caused by respiratory depression.

Medullary mu₂ receptors are thought to be responsible for the development of respiratory depression. Stimulation of these receptors diminishes chemoreceptor sensitivity to hypercapnia, resulting in loss of hypercarbic ventilatory stimulation.¹³ Activation of these receptors also decreases the central response to hypoxia¹³ and inhibits the medullary and pontine respiratory centers that regulate the rhythm of breathing.¹² The combination of these effects leads to prolonged pauses between breaths, periodic breathing, hypopnea, bradypnea, and in extreme cases, apnea. It is important to note that the initial manifestation of respiratory depression may be a hypopnea, with or without a decrease in respiratory rate.¹²

Patients do not develop complete tolerance to the respiratory depressant effects of the opioids.¹⁴ For example, patients enrolled in methadone maintenance therapy can experience chronic hypoventilation and hypercapnia.¹⁵ A ceiling effect on respiratory depression exists with partial agonist and agonist-antagonist opioids such as nalbuphine and buprenorphine.

Certain groups of patients are particularly sensitive to the ventilatory depressant effects of opioids. These groups include the elderly, patients with chronically elevated PaCO₂ (e.g., some patients with chronic obstructive pulmonary disease [COPD]), and patients with a depressed level of consciousness for other reasons. A strong painful stimulus sometimes can transiently overcome or prevent respiratory depression. Similarly, during procedural sedation (e.g., for orthopedic reductions) when pain is relieved, respiratory depression can become apparent. Bronchoconstriction also can occur, most likely as a result of histamine release as well as indirect effects on bronchiolar smooth muscle. Depression of ventilation also can occur in patients receiving neuraxial opioid administration; these effects may be delayed and may be accompanied by respiratory depression (see “Neuraxial Opioids”).

Seizures

Seizures are rare with therapeutic use of most opioids, the primary exception being tramadol. If seizures occur in the setting of an acute opioid overdose, hypoxia is likely the cause. Seizures are associated with meperidine, propoxyphene, and tramadol toxicity. These drugs are further discussed in a later section. In a mouse model, naloxone antagonized the convulsant effects of propoxyphene, but not those of meperidine or its metabolite, normeperidine.¹⁶ Fentanyl-induced myoclonus can resemble seizure activity, but true seizures are rarely caused by fentanyl.¹⁷

Musculoskeletal Effects: Truncal Rigidity and Movement Disorders

Intravenous (IV) administration of opioids has been associated with motor abnormalities ranging from increased tone to overt myoclonus and involving the chest wall and other truncal muscles. This complication is seen when large doses of highly lipophilic opioids such as fentanyl, sufentanil, remifentanil, or alfentanil are administered rapidly by the IV route.¹⁸ Whereas it was previously thought that opioid actions at the level of the spinal cord were responsible for this effect, it now appears that a central dopaminergic effect may be contributory. Both naloxone and neuromuscular blockade can overcome rigidity. Vocal cord spasm, although rare, can cause closure of the vocal cords, leading to difficult bag-valve-mask ventilation. As noted, myoclonic activity resembling seizure activity has been observed in patients after being rapidly infused with large doses of fentanyl.¹⁷ Serotonin syndrome, characterized by coarse tremors, increased muscular tone, myoclonus, agitation, and autonomic instability, has been associated with the use of both meperidine and dextromethorphan in combination with other serotonergic agents.

Cardiovascular Effects

The peripheral arterial and venous dilation caused by opioids appears to be mediated by both central depression of vasomotor centers and histamine release.¹⁹ Hypotension occurs more frequently in stressed individuals and in those with decreased intravascular volume. Histamine release occurs via non–immunoglobulin (Ig)E-mediated mast cell degranulation.²⁰ Different opioids produce different degrees of histamine release; for example, meperidine and morphine produce much greater release of histamine than fentanyl and sufentanil.²¹ The severity of histamine-mediated responses can be reduced by slowing the rate of infusion, and hypotension can be reduced by optimizing intravascular volume. Use of Trendelenburg position and saline infusion are appropriate initial interventions for opioid-associated hypotension.

Bradycardia is occasionally associated with opioid use and is most often secondary to decreased excitatory stimulation and hypoxia. Primary opioid-induced bradycardia is relatively rare and is thought to be related to increased vagal nerve activity. Morphine also can exert direct slowing effects on the sinoatrial and atrioventricular nodes.

Overall, there are no consistent effects of opioids on cardiac output or the electrocardiogram (ECG). Wide-complex dysrhythmias and impaired contractility are associated with propoxyphene overdose via sodium channel blockade (class Ia antidysrhythmic effect). Illicit opioid use sometimes is associated with cardiac effects secondary to adulterants or co-ingestants; examples are quinine and cocaine (“speedball”). Chronic high-dose methadone use is associated with prolongation of the QT interval.²²

Effects on Cerebral Circulation

There are minimal effects on cerebral circulation except in the setting of respiratory depression with hypoventilation and increased arterial partial pressure of carbon dioxide (PaCO₂). Increased PaCO₂ causes cerebral vasodilatation and increased cerebral blood flow, both of which can increase intracranial pressure. These effects are of importance for the treatment of head injuries or increased intracranial pressure from other causes. In the absence of hypoventilation, opioids actually decrease cerebral blood flow and possibly intracranial pressure.

Morphine

Morphine is the prototypical opiate. Its pharmacologic effects are primarily caused by binding to the mu opioid receptor and, to a much lesser extent, the delta and kappa opioid receptors. It is a potent analgesic with typical opioid side effects including sedation, respiratory depression, decreased GI motility, nausea and vomiting, histamine release, and miosis. Despite its efficacy, morphine has relatively poor penetration into the CNS, largely because of its low lipid solubility.

The principal pathway of morphine metabolism is via glucuronidation in the liver and kidneys. The active metabolite, morphine-6-glucuronide, is more potent than morphine and is largely excreted via the kidneys. Renal failure can lead to accumulation of this active metabolite, leading to unexpected toxic effects after even low doses.

Heroin

Heroin, also referred to as diacetylmorphine, is a highly lipophilic, semisynthetic opioid produced by acetylation of morphine. Heroin is a prodrug and is devoid of intrinsic opioid effects. It rapidly enters the CNS, where it is deacetylated to the active metabolites, monoacetylmorphine and morphine. Illicit heroin is typically administered by nasal insufflation, SQ injection (i.e., “skin popping”), smoking, or IV injection. The practice of inhaling vapors from heroin heated in aluminum foil is termed “chasing the dragon”; it is associated with a rapidly progressive, irreversible spongiform leukoencephalopathy.^23–25

Hydromorphone

Hydromorphone is a semisynthetic opioid that acts primarily at the mu receptor. It is a hydrated ketone derivative of morphine. Hydromorphone has become more popular in recent years in the emergency department, in postoperative and outpatient settings, and in the ICU. It is approximately 8 to 10 times more potent than morphine and may be associated with a lower risk of dependence. Hydromorphone also appears to have a better side-effect profile than morphine, as it tends to be associated with less nausea and pruritus.

Meperidine

Meperidine is a synthetic opioid that acts at both mu and kappa receptors. At equianalgesic doses, its side-effect profile is similar to morphine’s, except meperidine causes more euphoria and pronounced orthostatic hypotension from vasodilation and histamine release.

Of special note is meperidine’s extensive hepatic metabolism (90%) to normeperidine, a less potent analgesic eliminated via the kidneys. Normeperidine produces CNS excitation and is associated with myoclonus, delirium, and seizures. Metabolite accumulation occurs primarily in the context of escalating doses and renal failure.^26,27 Meperidine also blocks reuptake of serotonin by presynaptic neurons in the CNS, and by this mechanism may produce serotonin toxicity in patients who are taking monoamine oxidase inhibitors (MAOIs)²⁸ or other serotonergic drugs (see “Drug Interactions”).^29,30 The potential for these side effects, especially seizures, has led to a decline in the popularity of meperidine in many institutions.

Unique ICU uses for meperidine include suppression of shivering in postoperative patients, in patients undergoing therapeutic cooling/hypothermia, and in those receiving blood products or amphotericin. This effect is most likely mediated by changes in the shivering threshold.

Fentanyl, Alfentanil, Remifentanil, and Sufentanil

Fentanyl, alfentanil, remifentanil, and sufentanil are synthetic opioids of the 4-anilidopiperidine group. They are metabolized by the liver and subject to bioaccumulation with resultant prolonged clinical effects during continuous infusions.

Around the world, fentanyl is the most widely used of this group of drugs. It has a rapid onset and a short duration of effect and is an important drug for use in the ICU. Fentanyl’s peak effect occurs within 6 to 7 minutes after IV administration. Its very short half-life results from rapid distribution into inactive tissues such as fat, lungs, and skeletal muscle. Prolonged infusions or massive doses may lead to accumulation of the drug within these tissue reservoirs, resulting in prolonged duration of effect after discontinuation of the infusion. Lung uptake of up to 75% of a parenteral dose can occur and is often referred to as first-pass pulmonary uptake. Fentanyl is associated with fewer cardiovascular effects and histamine release than either morphine or meperidine.³¹ It undergoes extensive hepatic metabolism to norfentanyl, an active metabolite eliminated by the kidneys. Prolonged effects can be seen in the elderly and in patients with renal impairment. Fentanyl-associated myoclonus may resemble seizure activity, but EEGs recorded in these patients failed to show seizure activity.¹⁷ Muscle rigidity, particularly of the chest wall, may hamper spontaneous or assisted ventilation. Although this effect can be reversed with naloxone, administration of naloxone simultaneously reduces the analgesic effect of fentanyl.

Sufentanil is a fentanyl analog and 5 to 10 times more potent as an analgesic than fentanyl. Sufentanil offers the advantage of even greater hemodynamic stability, and it is an analgesic of choice in cardiac surgery. Following cessation of a prolonged infusion, persistent sedation is not as prominent with sufentanil as it is with fentanyl. Sufentanil should be considered a practical and appropriate analgesic option for use in selected cases in the ICU.

Alfentanil has the shortest duration of action and the most rapid onset of this group. Alfentanil’s unique metabolism by hepatic cytochrome P4503A (CYP3A4 and 5) enzymes render its metabolism variable and unpredictable. Polymorphisms in the genes coding for these cytochromes and inhibition by other drugs, including some macrolide antibiotics, protease inhibitors, and antifungal agents, such as fluconazole, can make its effects less consistent, particularly when administered by prolonged infusion.^32,33

Remifentanil is an ultra-short-acting mu opioid receptor agonist with a unique pharmacokinetic profile. Though it is a 4-anilidopiperidine like fentanyl, alfentanil, and sufentanil, remifentanil is metabolized directly by nonspecific blood and tissue esterases to remifentanil acid (RA). RA is a relatively inactive metabolite. Remifentanil has a terminal half-life of approximately 10 to 20 minutes and a context-sensitive half-life of 2 to 4 minutes, even following prolonged infusions. Time to extubation in mechanically ventilated ICU patients is remarkably short after discontinuing remifentanil (15-45 minutes).^34–36 This effect is preserved regardless of the presence of other drugs, disease, or organ failure.^37,38 Despite RA’s predominantly renal elimination, and unlike fentanyl and its analogs, renal impairment does not appear to significantly affect time to extubation in patients on continuous infusions of remifentanil.^35–3739 The properties of organ-independent metabolism, lack of accumulation, and precision and predictability of onset and offset make remifentanil a promising sole agent or combined agent (often with propofol or midazolam) in analgesia-based sedation in ventilated ICU patients.^35–44 As with other opioids, bradycardia, hypotension, muscle rigidity and nausea can occur with remifentanil. Limiting boluses to 0.5 µg/kg is suggested to decrease the incidence of muscle rigidity.³⁵ Whether remifentanil, like other opioids, can reduce cortisol release—a well-established phenomenon in mechanically ventilated and sedated ICU patients—has yet to be determined.⁴⁵ A recent meta-analysis of remifentanil infusions compared to other regimens in mechanically ventilated ICU patients showed no significant benefit on outcomes such as duration of mechanical ventilation, length of stay, or mortality.³⁶ Remifentanil injections contain glycine and should not be given via neuraxial routes (epidural or intrathecal). Dosing should be based on ideal body weight in obese patients.

Methadone

Methadone is a synthetic opioid with high oral bioavailability and a prolonged duration of action (>24 hours). Its most common use is in substitution therapy for opioid dependence. It is also used as an analgesic in patients with chronic pain. Methadone is hepatically metabolized to inactive metabolites that undergo urinary and biliary excretion. Overall, its side-effect profile resembles that of morphine, although the (desirable and undesirable) effects of methadone persist for substantially longer. Methadone causes less euphoria and less sedation than other opioids. Tolerance to methadone may require escalating doses when it is used for prolonged periods. Methadone at high doses can prolong the QT interval and increase the risk of torsades de pointes.²²

Buprenorphine

Buprenorphine is a partial agonist that has 50 times greater affinity for the mu opioid receptor than morphine. It is therefore relatively resistant to antagonism by naloxone and can displace other opioids from mu opioid receptors. It is rarely used as an analgesic but is slowly replacing methadone as the standard agent for substitution therapy in patients with opioid abuse (i.e., Subutex, Suboxone). Because it is a partial mu opioid agonist, there may be less ventilatory depression associated with buprenorphine than with full agonist opioids; a “ceiling effect” exists such that no further respiratory depression occurs beyond a certain dose range. Nevertheless, buprenorphine can still be abused, and particularly when abused in combination with other respiratory depressants, its use can be lethal.

Naloxone

Naloxone is a pure competitive antagonist at mu, delta, and kappa opioid receptors. It is commonly used in both prehospital and hospital settings to reverse opioid-induced respiratory depression. The typical prehospital dose of naloxone employed by emergency medical service personnel to treat respiratory depression and/or coma is in the range of 0.4 to 2 mg (IM or IV). However, these high doses often precipitate a dramatic and dangerous withdrawal syndrome in tolerant individuals. Vomiting, aspiration, and severe agitation are common with antagonist-precipitated acute withdrawal (see “Opioid Overdose”). Aspiration is a particular risk after use of naloxone in opioid-dependent patients who have nonopioid causes for their depressed level of consciousness. In these patients, naloxone produces vomiting but does not fully awaken the patient, predisposing to aspiration. It appears to be safer and equally effective in most situations to administer 0.04 to 0.05 mg (40-50 µg) IV and titrate upwards at similar doses every 2 to 3 minutes while providing ventilatory support as needed until the desired clinical response is attained.

Some sources recommend the use of low-dose naloxone infusions (0.25 µg/kg/h) to protect against ventilatory depression and decrease symptoms of pruritus, nausea, and vomiting in patients receiving continuous opioid infusions, in addition to augmenting analgesia.⁶ In the ICU setting, this approach may benefit patients who are receiving patient-controlled analgesia (PCA) or neuraxial (i.e., epidural or spinal) analgesia.

Of note, orally administered naloxone has very poor bioavailability because of an extensive first-pass effect and therefore produces minimal if any systemic effects. It is included in some oral analgesic preparations as a deterrent to parenteral abuse (see Table 184-3).

Methylnaltrexone and Alvimopan

Methylnaltrexone and alvimopan have been approved recently by the U.S. Food and Drug Administration (FDA) and are members of a new class of drugs: peripherally acting mu opioid receptor antagonists (PAMORAs). In contrast to naloxone, these newly approved drugs do not cross the blood-brain barrier and therefore do not antagonize the central (analgesic) effects of opioids. They act on peripheral opioid receptors only, blocking side effects such as constipation and ileus while preserving centrally mediated analgesia.^46–49 Methylnaltrexone (SQ) is also used for the treatment of opioid-induced constipation in patients with advanced cancer and AIDS.^50–52 It is administered via the SQ route, although experimentally, higher doses of enteric-coated formulations have been effective in increasing GI motility. Alvimopan (PO) has been approved for the treatment of postoperative ileus following bowel resection.⁵³ PAMORAs, as members of a novel drug class, have led to some realizations concerning the peripheral versus central effects of opioids. It appears that GI motility, pruritus (partly), nausea and vomiting, cough reflex (partly), and urinary retention may be mediated by peripheral opioid receptors. Chronic constipation in patients on chronic methadone maintenance is another area of research.^46–49 Interestingly, effects mediated through activation of peripheral opioid receptors also have been implicated as promoting decreased cellular immunity, increased angiogenesis, increased vascular permeability, and increased bacterial lethality (particularly Pseudomonas aeruginosa).⁴⁶ These are areas of active research in both the basic science and clinical arenas.

Tolerance, Dependence, and Withdrawal

Tolerance and dependence are inevitable features of chronic opioid use. Tolerance refers to decreasing effectiveness and the need for higher doses with repeated use, whereas dependence refers to the occurrence of withdrawal symptoms on cessation of the drug. Cross-tolerance exists between various opioids but is imperfect. Tolerance usually takes 2 to 3 weeks to develop with analgesic doses of morphine and can occur without dependence. Some mild degree of physical dependence can occur after as brief a period as 48 hours of continuous medication. This consideration is important in the care of patients using PCA devices and symptomatic heroin body packers (individuals who ingests wrapped packets of illicit drugs to transport them).

Although tolerance, dependence, and abuse of opioids for the treatment of pain syndromes can be significant issues in clinical practice, undertreatment in patients with pain for fear of tolerance and dependence is a common mistake made by clinicians. The vast majority of patients can be treated effectively if clinical guidelines for opioid prescription are followed. If tolerance and dependence to opioid analgesics exists, patients may require very large doses to achieve a therapeutic effect. Consultation with a pain management specialist may be warranted for such individuals. Patients on a high-dose chronic methadone regimen are at risk for QT-interval prolongation.

The opioid withdrawal syndrome (OWS) encompasses a consistent cluster of symptoms including initially abdominal cramps, yawning, lacrimation, piloerection, coryza, restlessness, and drug craving and later progressing to nausea, vomiting, and diarrhea. Altered mental status is rarely present in spontaneous OWS but is common in patients with OWS precipitated by administration of an opioid antagonist. Onset and duration of OWS varies with the duration of effect of the implicated opioid. Although it can be extremely distressing to the patient, OWS typically is not life threatening. Exceptions are acute withdrawal precipitated by large doses of an opioid antagonist in dependent individuals and opioid withdrawal in neonates. Treatment options for OWS include supportive care, treatment with antiemetics and clonidine (a centrally acting α₂-agonist that diminishes CNS symptoms), or administration of an opioid agonist, typically methadone. Administration of morphine and/or replacement of the prescribed opioid may be sufficient in a patient who is withdrawing from opioids taken for chronic pain.

Opioid Overdose

Classic findings in patients with opioid toxidromes are miosis, diminished bowel sounds, CNS depression, and respiratory depression; coma and apnea can be present in extreme cases. The major cause of death in opioid overdose is respiratory depression. Other complications are usually secondary to hypoxia (e.g., seizures, dysrhythmias, brain injury). Many patients with opioid overdose require admission to an ICU for monitoring, medical management, or respiratory support.

Naloxone, administered appropriately to reverse symptoms of respiratory depression, can obviate the need for endotracheal intubation in most cases. For example, for opioid overdoses in opioid-dependent patients (e.g., users of prescription analgesics, heroin, or methadone), a starting dose of 0.05 mg IV is indicated, using ventilatory support and rapid titration to higher doses as necessary. The endpoint of reversal should be adequate respiration, not complete reversal of sedation.⁵⁴ High doses of naloxone (e.g., 1 to 2 mg IV) may be used safely in nontolerant individuals. Continuous infusions may be appropriate for patients who have overdosed with long-acting opioids.^55,56 Symptomatic opioid body packers (i.e., people hired to swallow large amounts of tightly wrapped heroin packets and smuggle them across international borders) are likely to require continuous naloxone infusions until the packets are passed or removed.⁵⁶ Keeping symptomatic patients awake (with naloxone), administering whole-bowel irrigation using polyethylene glycol/electrolyte lavage solution at 0.5 to 2 L/h, and using a bedside commode can facilitate the patient’s passage of the packets. Tolerance and dependence can occur in these patients if “leaking” is protracted. Body packers usually are not opioid users themselves.⁵⁶

There is some suggestion that the catecholamine surge associated with rapid reversal with naloxone in tolerant individuals can precipitate acute lung injury (i.e., acute noncardiogenic pulmonary edema). Dog models of opioid overdose suggest that hypercapnia may worsen the catecholamine release associated with naloxone administration hemodynamics.^57,58 Adequate ventilation to normalize PaCO₂ before antagonist administration is suggested to prevent hemodynamic instability. However, no single mechanism is sufficient to explain the development of opioid-associated pulmonary edema, and multiple factors are likely involved. There is an association between naloxone administration and the clinical diagnosis of pulmonary edema. The typical clinical presentation is an obtunded patient with profound respiratory depression who awakens either spontaneously or as the result of antagonist administration. In these situations, it is possible that patients with heroin overdose develop acute lung injury as a result of their respiratory depression or apnea, and that naloxone administration merely unmasks the effects of the opioid by restoring spontaneous respirations.⁵⁹ This model proposes that hypoxic pulmonary endothelial damage occurs during near-apneic periods. Acute lung injury and/or noncardiogenic pulmonary edema associated with opioid overdose should be treated with standard therapies and supportive care.

If acute withdrawal is precipitated by naloxone, supportive care is recommended. Sedation of an agitated patient experiencing acute withdrawal due to administration of naloxone often leads to even more profound sedation, leading to the necessity for endotracheal intubation once the effects of naloxone wane in 30 to 45 minutes. Withdrawal following naltrexone, a long-acting opioid antagonist, is more complex; some advocate high-dose opioid infusion to overcome the competitive antagonism.⁶⁰

Many illicit drug users “co-ingest” other drugs of abuse such as cocaine (i.e., speedball), amphetamines, and benzodiazepines with opioids. The presence of one or more of these other drugs in the system can complicate the clinical presentation, and their toxic effects may be unmasked after the administration of naloxone. It is important to note that not all opioid-intoxicated patients present with miosis. Severe systemic hypoxia and presence of co-ingestants can produce normal-sized or dilated pupils.

Currently, no role has been established for methylnaltrexone and/or alvimopan in acute overdoses or symptomatic opioid body packers. Their lack of central effects, specifically lack of reversal of CNS and respiratory depression, routes of administration (SQ and PO, respectively), and prolonged duration of effects may limit their appropriateness in such cases.

Acetaminophen and acetylsalicylic acid (ASA) are common ingredients in analgesic combinations, and the presence of these drugs in the serum should be actively sought in any patient with a suicide attempt by overdose.

Consultation with a medical toxicologist or poison control center is strongly recommended for all cases of serious opioid overdose, especially those involving body packers, continuous-release preparations, ECG changes, or severe respiratory depression. Similar consultation is advised when caring for patients with antagonist-precipitated OWS.

Drug Interactions

Opioids given in combination with either sedative-hypnotics (e.g., benzodiazepines) or propofol can have a synergistic effect on systemic vascular resistance,⁶¹ level of sedation, and respiratory depression.^61–65

Meperidine and dextromethorphan are associated with serotonin toxicity. This syndrome typically develops in patients who are simultaneously taking two proserotonergic drugs. Some commonly prescribed proserotonergic drugs include MAOIs, selective serotonin reuptake inhibitors (SSRIs), valproic acid, lithium, clonazepam, and buspirone. Patients taking proserotonergic drugs should not receive meperidine or dextromethorphan.^28–3066 Morphine, fentanyl, and methadone are not associated with serotonin syndrome.

Neuraxial Opioids

The term neuraxial opioids refers to administration of opioids into the epidural or subarachnoid space (“spinal”). The use of neuraxial opioids is common in the care of postoperative and traumatized patients in an intensive care setting. To exert their clinical effects, opioids have to diffuse across the dura and gain access to the substantia gelatinosa of the spinal cord. Opioid receptors in the spinal cord are of the mu, delta, and kappa type.

Neuraxial opioids tend to be associated with fewer systemic effects when compared with orally or parenterally administered opioids. Some highly lipophilic opioids (e.g., fentanyl, sufentanil) diffuse into the systemic circulation so quickly that their use in neuraxial analgesia offers little benefit over IV use. For other opioids, especially morphine and meperidine, systemic effects are usually caused by a combination of systemic absorption and cephalad migration of drug into the CNS. Typically, 5 to 10 times the dose used for spinal analgesia is required for epidural analgesia. Care should be taken to avoid inadvertent overdosing, which can occur if doses appropriate for epidural analgesia are injected into the subarachnoid space.

The common side effects of neuraxially administered opioids are pruritus, nausea and vomiting, urinary retention (via inhibition of parasympathetic neurons located in the sacral spinal cord), and ventilatory depression. Although early ventilatory depression rarely occurs, depression occurring within 2 hours after administration most likely represents systemic absorption of a lipid-soluble opioid. Delayed respiratory depression can be seen as long as 6 to 12 hours after neuraxial administration and most likely represents cephalad migration of opioid into the CNS.⁶⁷

In general, neuraxial use of opioids should be considered safe and effective. Care should be taken with their use, because neuraxial opioid administration can cause CNS and systemic side effects. Most side effects respond to parenteral naloxone. The future role for PAMORAs in this setting has yet to be determined.

The Patient with Pain

In the ICU, analgesic requirements can be substantial, and opioids are often chosen because of their efficacy and predictability. Morphine, hydromorphone, fentanyl, sufentanil, and remifentanil are among the most commonly used opioids in the ICU setting. All modes of delivery are associated with systemic side effects. A more complete discussion of analgesia may be found in Chapter 3.